title: Safety and tolerability of different titration rates of retigabine (ezogabine) in patients with partial-onset seizures.
abstract: Retigabine (RTG; international nonproprietary name)/ezogabine (EZG; US adopted name) is an antiepileptic drug (AED) that prolongs neuronal voltage-gated potassium-channel KCNQ2-5 (Kv 7.2-7.5) opening. This double-blind study evaluated different RTG/EZG dose-titration rates. Patients (N=73) with partial-onset seizures receiving concomitant AEDs were randomized to one of three titration groups, all of which were initiated at RTG/EZG 300mg/day divided into three equal doses. Fast-, medium-, and slow-titration groups received dose increments of 150mg/day every 2, 4, and 7 days, respectively, achieving the target dose of 1200mg/day after 13, 25, and 43 days, respectively. Safety assessments were performed throughout. Discontinuation rates due to treatment-emergent adverse events (TEAEs) were numerically higher in the fast- (10/23) and medium- (7/22) titration groups than in the slow-titration group (3/23) but statistical significance was achieved only for the high-titration group compared with the low-titration group (p=0.024). Stratified analysis, with concomitant AEDs divided into enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) or noninducers, showed that the risk of discontinuation due primarily to TEAEs was significantly higher in the fast- (p=0.010) but not in the medium-titration group (p=0.078) when compared with the slow-titration group. Overall, the slow-titration rate appeared to be best tolerated and was used in further efficacy and safety studies with RTG/EZG.
authors.affiliation: Arkansas Epilepsy Program, 2 Lile Ct, Ste 100, Little Rock, AR 72205, USA. Electronic address: vbiton@clinicaltrialsinc.com.
authors.forename: Victor
authors.initials: V
authors.lastname: Biton
authors.forename: Antonio
authors.initials: A
authors.lastname: Gil-Nagel
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Brodie
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Derossett
authors.forename: Virinder
authors.initials: V
authors.lastname: Nohria
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010655:Phenylenediamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine
keywords: Adverse events; Epilepsy; Ezogabine; Retigabine; Safety; Titration rates